Antipsychotic deflates the brain

Drug for schizophrenia causes side effects by shrinking part of the brain.

Amy Maxmen

A commonly-prescribed antipsychotic drug shrinks the brain within hours of administration.Jim Wehtje / Photodisc / Getty Images

A leading antipsychotic drug temporarily reduces the size of a brain region that controls movement and coordination, causing distressing side effects such as shaking, drooling and restless leg syndrome.

Just two hours after injection with haloperidol, an antipsychotic commonly prescribed to treat schizophrenia, healthy volunteers experienced impaired motor abilities that coincided with diminished grey-matter volume in the striatum¹ — a brain region that mediates movement.

"We've seen changes in the brain before, but to see significant remodelling of the striatum within a couple of hours is staggering," says Clare Parish at the Howard Florey Institute for brain research in Melbourne, Australia, who was not involved in the study. "Our viewpoint was that only chemical changes would happen in such a short time."

In functional magnetic resonance imaging (fMRI) scans the authors observed the participants' striatal volume diminishing and changes to the structure of the motor circuitry in their brains. Further, their reaction times slowed in a computer test taken after the treatment, indicating the onset of lapses in motor control that affect many patients on antipsychotics.

Dopamine downsizing

Haloperidol has a number of side effects, although many of these are minor and recede within weeks of starting treatment. With few better alternatives, psychiatrists have prescribed the drug for more than 40 years to treat people suffering from hallucinations, delirium, delusions and hyperactivity.

Like most antipsychotics, haloperidol blocks the D2 receptor, which is sensitive to dopamine. The drug stifles the elevated dopamine activity that is thought to underlie psychosis. D2 receptors are abundant in the striatum, where their activity regulates gene expression. But, until now, no one knew that blocking the receptors would rapidly alter the brain's physical structure.

Haloperidol shrank volunteers' striatums in two hours, but they bounced back within a day.Tost, H et al.

"This is the fastest change in brain volume ever seen," says Andreas Meyer-Lindenberg, professor of psychiatry and psychotherapy at the University of Heidelberg in Mannheim, Germany, and a lead author on the report inNature Neuroscience¹. "Studies have found that the volume of brain regions changes over a number of days, but this is in one to two hours, and in half that time it bounces back."

Within a day, volunteers' brains returned to almost their original size as the effects of the single haloperidol dose subsided. Meyer-Lindenberg says this result should alleviate fears that the drug destroys brain cells. "We know it's not killing neurons because the brain rebounds," he says.

Instead, the team suggests that haloperidol downsizes synapses, the junctions through which neurons communicate. Meyer-Lindenberg speculates that the change is mediated by the protein BDNF, which is involved in synapse growth and diminishes in response to antipsychotic treatments in mice.

The bigger picture

"I think this study will cause worry to some," says Shitij Kapur, dean of the Institute of Psychiatry at King's College London. To counteract those fears, he notes that the brain changes caused by the drug seem to be reversible and that the dose used in the study was a little higher than that usually given to patients who had not taken the drug before.

 

The findings may also hint at why people with bipolar disorder have reduced grey matter in parts of their brains after manic mood swings². Andrew McIntosh at the University of Edinburgh, UK, says that the connection between the brain-shrinking effects of an antipsychotic reported in this study and the grey-matter reduction he and others have observed in schizophrenic and bipolar patients is "a bit uncertain but this paper definitely makes this worthy of further investigation".

Furthermore, D2 receptors in parts of the striatum have been associated with addiction. This has led Parish to ponder on whether structural changes underlie reward-seeking behaviours. "You wonder what sort of acute changes happen through those receptors in the addicted brain because you hear of cases where addiction happens after just one exposure," she says. 

References

1. Tost, H. et al. Nature Neurosci. doi:doi:10.1038/nn.2572 (2010).
2. Moorhead, T. et al. Biol. Psychiatry 62, 894-900 (2007). | Article | PubMed

 

http://www.nature.com/news/2010/100606/full/news.2010.281.html

If drinking and smoking seem inextricably linked, perhaps it's because in the brain's pleasure centre they actually are.

Alcoholics often have a particularly hard time quitting cigarettes. Traute Flatscher-Bader at the University of Queensland in Brisbane, Australia, and colleagues wondered why this should be. So they did a post-mortem analysis of gene expression in the brains of smokers, alcoholics and those who had done both during their lives.

They found that a group of genes in the nucleus accumbens - an area involved in creating pleasurable feelings - were expressed most strongly in their group of alcoholic smokers (Alcoholism: Clinical and Experimental Research, DOI: 10.1111/j.1530-0277.2010.01207.x).

These genes play a role in rewiring the neurons in the nucleus accumbens. That means people who both smoke and drink might get a greater reward, making it harder for them to quit, says Flatscher-Bader.

Knowing that the link between drinking and smoking may not be purely social could lead to new ways to treat addiction.

http://www.newscientist.com/article/mg20627634.700-trying-to-quit-smoking-the-devil-is-in-the-drink.html

http://videos.arte.tv/fr/videos/les_premiers_europeens-3253158.html

43' de film sur arte

Out of the shadows: our unknown immune system

• 02 June 2010 by Linda Geddes, Baltimore
• Magazine issue 2763. Subscribe and save

Editorial: Tread carefully in the immune system's shadowlands

DELIBERATE infection with a blood-sucking worm seems an odd way to treat multiple sclerosis (MS). Yet more surprising is what this experiment may tell us about a "shadow" branch of our immune system. Completely unknown until recently, this is pointing to new ways of treating a host of complex diseases.

A couple of recent studies suggest that parasitic infection dampens inflammation and reduces relapse rates in people with MS, in which the body's own cells are attacked by the immune system as if they were "foreign". So Cris Constantinescu at the University of Nottingham, UK, and his colleagues plan to place tiny hookworm larvae on the skin of 32 people with MS, allowing the worms to burrow down and infect the volunteers.

The team won't just be looking for a reduction in volunteers' symptoms though. They will also be watching to see if the parasites boost numbers of a set of newly discovered immune cells, known as regulatory B cells (B regs).

B regs are sending shockwaves through the immunology community. Until recently it was assumed that B cells' main role was to make antibodies at the behest of T-cells. These master regulators enhance or suppress an immune attack depending on the situation, as well as carrying out immune attacks in their own right (See diagram). It was therefore thought that T-cells are at fault when the body attacks itself in autoimmune diseases, such as MS, asthma, diabetes and rheumatoid arthritis - and when it fails to route out disease agents, such as cancer cells.

Now it seems that T-cells are not the immune system's only regulators. Experiments suggest that under some circumstances, B regs regulate T-cells, providing a shadow role for B cells.

"Diseases we've traditionally thought to be mediated by T-cells might actually be regulated by B cells," says Kevan Herold of Columbia University in New York. Boosting B regs might therefore provide new opportunities for treating autoimmune diseases, while inhibiting B regs it could be a new way to treat cancer.

Animal studies are already suggesting that the approach might work in one type of asthma. In a study published in May, Padraic Fallon of Trinity College, Dublin, and his colleagues isolated B regs from the spleens of mice infected with the parasite Schistosoma mansoni. When they transferred the B cells into mice primed to develop asthma, this either reduced their symptoms or stopped them developing asthma in the first place (The Journal of Allergy and Clinical Immunology, DOI: 10.1016/j.jaci.2010.01.018).

"These are major regulators of the immune system in allergic disease," Fallon concludes. B regs seemed to work by releasing a chemical called IL-10 into the lungs, drawing in regulatory T- cells (T regs), which in turn inhibited immune attacks.

IL-10 played a similar role in a subset of B regs, which Thomas Tedder at Duke University School of Medicine in Durham, North Carolina, calls B10 cells. His team found that transferring these cells into mice with a disease similar to multiple sclerosis reduced the severity of disease.

Tedder has also identified similar cells in humans. "We can stimulate them and we can isolate them, but they're fairly rare," he says. He presented both findings in May at the annual American Association of Immunologists meeting in Baltimore, Maryland.

The race is now on to identify drugs that might boost B regs in people with autoimmune diseases or suppress them in people who have cancer.

One clue that such an approach might work comes from studies of rituximab, which kills B cells. First prescribed for the treatment of B cell lymphoma, a type of cancer, the drug has also reduced symptoms in people with diabetes, MS and rheumatoid arthritis. Rituximab most likely knocked out all the B cells to start with, and then, for some reason only the B regs grew back, which helped suppress autoimmunity, suggests Frances Lund of the University of Rochester Medical Center in New York (Nature Reviews Immunology, DOI: 10.1038/nri2729).

In individuals with cancer, however, it might be desirable to suppress B regs. Preliminary evidence suggests that as well as keeping autoimmunity in check, B regs also help dampen the immune system's natural ability to recognise and destroy tumours.

Tedder's team has already created antibodies that can deplete B10 cells - but not other B cells - in mice, and says he has similar antibodies that may selectively deplete human B10 cells - although he hasn't yet tested them in people.

Arya Biragyn of the US National Institute of Aging, and his colleagues, also announced at the Baltimore meeting that they have identified a separate set of B regs that cancer seems to recruit in order to avoid detection by the immune system. Destroying these cells might make let's hope you have deep pockets cancer immunotherapies work better.

"Even if you transiently wipe out B cells during immunotherapy, this should give you very potent anti-tumour responses against hidden tumour cells," Biragyn says.

Working out how parasitic worms trigger B reg activity might suggest additional ways to do this - and to boost B regs. Indeed, Fallon has identified several molecules released by parasitic worms that seem to trigger B regs.

Until such drugs are developed, parasites might be the best way to boost B regs. Severe hookworm infection can cause malnutrition, internal bleeding and anaemia, but in a mild and controlled infection, the dangers are minimal, says Constantinescu, though there may be some itchiness as the worms go through the skin.

Editorial: Tread carefully in the immune system's shadowlands

Zoologger: Judge Dredd worm traps prey with riot foam

• 00:01 02 June 2010 by Michael Marshall
• For similar stories, visit the Zoologger and Weapons Technology Topic Guides

Species: Euperipatoides rowelli

Habitat: New South Wales, Australia, loitering in gangs on rotting logs

Among proponents of non-lethal weapons, one of the most widely discussed technologies is "sticky foam", pioneered by Judge Dredd as "riot foam" in the British comic 2000 AD. Fired from a high-powered gun, it rapidly solidifies on contact, immobilising the victims but – hopefully – not killing them.

As ever, nature got there first. Strange creatures called velvet worms use a similar trick to entrap their prey, and while the immobilisation process might not be fatal, the subsequent process of being eaten most certainly is.

Velvet worms are onychophorans and are truly ancient: they were around in the Cambrian period over 500 million years ago, and were among the first land animals to take up walking. Nowadays there are about 90 species left, and E. rowelli is one of the most remarkable.

The worm that turned

They're not your typical worms. For a start, they have legs – lots of them. The group is distantly related to nematode worms, but is probably closer to the arthropods, the group that includes insects and centipedes. In a bad light, velvet worms look like bulbous centipedes without exoskeletons, and their brains are similar to those of chelicerates, a subgroup of the arthropods that includes spiders and scorpions.

What E. rowelli lacks in size – it is 1 to 3 centimetres long – it makes up for in naked aggression. The worms live in groups of around 15 individuals, nestled together in cavities in rotting logs. The groups are dominated by the females, which give birth to live young and are larger than the males. However, it is actually the males that start the groups, by releasing a pheromone which attracts females and other males to join them.

Not only do they live in groups, they hunt in packs. Their usual victims are small insects like termites, but they sometimes go for animals much larger than themselves, such as grasshoppers.

Once the prey is immobilised by sprays of slime, one of the worms finds a soft spot and injects the victim with saliva, which kills it and begins digesting its insides. While they wait for dinner to be ready, the worms eat the slime up again so as not to waste it.

When it comes to the main course, there is a strict feeding hierarchy, with the dominant female feeding alone for the first hour. Then other females are allowed to chow down, and finally the males and juveniles.

Slime time

So how does the riot foam work? Victoria Haritos of the research institute CSIRO Entomology in Canberra, Australia, and colleagues decided to find out by studying its chemistry.

Given that velvet worms are related to the arthropods, you might expect their slime to be similar to the silks produced by spiders and moths – but you would be wrong. Insects and spiders produce highly structured proteins, but the proteins in E. rowelli's slime are almost entirely unstructured and disordered.

As far as we know, the mechanism is unique, and it works something like this. The slime is mostly water, and because the proteins are disordered they expose a great many electrically charged regions to the liquid, ensuring that they stay fully dissolved as long as the slime is held in the slime glands.

But as soon as the slime is squirted – from limbs modified into sprayguns and mounted either side of the head – the water starts evaporating and the proteins start to come out of solution. This then triggers two mechanisms that trap the unfortunate prey.

First, the insect's struggles pull some of the proteins out into threads that wrap around its body. At the same time, the loss of water causes the slime to transform into a hard, brittle solid: a glass.

Readers who remember the resinous cocoons used to trap luckless humans in the movie Aliens may find this oddly familiar.

Journal reference: Proceedings of the Royal Society B, DOI: 10.1098/rspb.2010.0604

Read previous Zoologger columns: Flashmobbing locusts have redesigned brains , Smart camo lets glow-in-the-dark shark hide, Attack of the self-sacrificing child clones, The most kick-ass fish in the sea, The most bizarre life story on Earth?, Keep freeloaders happy with rotting corpses, Robin Hood meets his underwater match, The mud creature that lives without oxygen, Magneto-bat steers by a built-in compass.

Image: O. Louis Mazzatenta/National Geographic/Getty

http://www.newscientist.com/article/dn18987-zoologger-judge-dredd-worm-traps-prey-with-riot-foam.html